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Cytokine network in the human central nervous system Lee, Yong Beom


Expression of various cytokines and their receptors in human CNS neurons and glial cells in culture was investigated using RT-PCR, ELISA and immunoblotting. Pure populations of astrocytes, microglia and neurons were prepared from mixed cell cultures isolated from brains of human embryos (12-18 weeks' gestation), and oligodendrocytes were prepared from adult human brain tissues. RT-PCR results of cytokines and their receptors were as follows: (1) Non-stimulated astrocytes expressed transcripts for IL-9, IL-11, IL-15, TGF-α, TGF-β1, CNTF, LIF and SCF. Treatment with IL-1β and IFN-γ induced expression of IL-1β, IL-6, IL-8, TNF-α and GM-CSF and increased expression of IL-9 and IL-15 in astrocytes. Transcripts for IL-1RI, IL-6R, IL-8R, IL-9Rα, IL-10Rα, IL-11R, IL-12Rβ2, IL-13Rα, IL-15Rα, TNFRI, SCFR and gp130 were detected in unstimulated astrocytes, while expression of IL-1RII and TNFRII was induced following stimulation with IL-1β and IFN-γ. (2) In unstimulated microglia, low levels of transcripts for IL-lβ, IL-6, IL-10, IL-15, TNF-α, TGF-α, TGF-β1, and IL-1RI, IL- 1RII, IL-6R, IL-8R, IL-9Rα, IL-10Rα, IL-12Rβ2, IL-13Rα, IL-15Rα, TNFRI, TNFRII and gp130 were detected. Treatment of microglia with LPS and IFN-γ induced expression of IL-8 and IL-12 and increased expression of transcripts for IL-1β, IL-6, IL-10, IL-15 and TNF-α. (3) Neurons expressed transcripts for IL-5, TGF-β1, LIF, and IL-9Rα, IL-9Rα, IL-13Rα, TNFRI and gpl30. (4) Oligodendrocytes expressed transcripts for IL-1β, TGF-α, TGF-β1 and CNTF, and for IL-1RI, 1L-6R, IL-8R, IL-9Rα, IL-13Rα, TNFRII, SCFR and gp130. Secretion of selected cytokines from astrocytes and microglia was determined by ELISA and immunoblotting. (1) In astrocytes, treatment with IL-1β resulted in increased levels of IL-6, IL-11, IL-15, but not with IFN-γ. IL-9 was secreted constitutively, and its protein level was not changed with IL-1β or IFN-γ. (2) In microglia, IL-6 secretion was increased by LPS treatment, but not by IFN-γ or TNF-α. As well, IL-15 secretion was increased by LPS or IFN-γ treatment. TNF-α secretion was increased by treatment with LPS, and demonstrated a synergistic effect with IFN-γ for TNF-α production. Effects of selected cytokines were studied on NO and TNF-α production in astrocytes and microglia respectively. IL-10 inhibited the TNF-α production (>90%) in LPS/IFN-γ- treated microglia. NO production in IL-1β/IFN-γ-treated astrocytes was not altered by any of the cytokines examined. In addition, p38 MAP kinase was found to be involved in the upregulation of TNF-α mRNA in microglia, while in IL-1β-treated astrocytes it was involved in the upregulation of translation of TNF-α mRNA. Selected cytokines including IL-9, IL-11 and IL-15 showed neurotrophic activities such as neuronal differentiation and survival of human embryonic neurons.

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